Sphingolipid metabolism and neutral sphingomyelinases

Sphingolipids are an important class of lipid molecules that play fundamental roles in our cells and body. Beyond a structural role, it is now clearly established that sphingolipids serve as bioactive signaling molecules to regulate diverse processes including inflammatory signaling, cell death, proliferation, and pain sensing. Sphingolipid metabolites have been implicated in the onset and progression of various diseases including cancer, lung disease, diabetes, and lysosomal storage disorders. Here we review sphingolipid metabolism to introduce basic concepts as well as emerging complexities in sphingolipid function gained from modern technological advances and detailed cell and animal studies. Furthermore, we discuss the family of neutral sphingomyelinases (N-SMases), which generate ceramide through the hydrolysis of sphingomyelin and are key enzymes in sphingolipid metabolism. Four mammalian N-SMase enzymes have now been identified. Most prominent is nSMase2 with established roles in bone mineralization, exosome formation, and cellular stress responses. Function for the other N-SMases has been more enigmatic and is an area of active investigation. The known properties and potential role(s) of each enzyme are discussed to help guide future studies.